TY - JOUR
T1 - A computationally designed inhibitor of an Epstein-Barr viral Bcl-2 protein induces apoptosis in infected cells
AU - Procko, Erik
AU - Berguig, Geoffrey Y.
AU - Shen, Betty W.
AU - Song, Yifan
AU - Frayo, Shani
AU - Convertine, Anthony J.
AU - Margineantu, Daciana
AU - Booth, Garrett
AU - Correia, Bruno E.
AU - Cheng, Yuanhua
AU - Schief, William R.
AU - Hockenbery, David M.
AU - Press, Oliver W.
AU - Stoddard, Barry L.
AU - Stayton, Patrick S.
AU - Baker, David
N1 - Funding Information:
This work was supported by the National Institute of General Medical Studies of the National Institutes of Health (NIH) under award numbers P41GM103533 and R01GM49857; NIH grants R21EB014572, R01CA076287, and R01CA154897; the Washington State Life Sciences Discovery Fund grant 2496490 to the Center for Intracellular Delivery of Biologics; the Defence Threat Reduction Agency; and a grant by the David and Patricia Giuliani Family Foundation. Computational resources were provided by BOINC and supported by the National Science Foundation through awards SCI-0221529, SCI-0438443, SCI-0506411, PHY/0555655, and OCI-0721124. P.S.S. and O.W.P. are cofounders of PhaseRx Pharmaceuticals, which has licensed drug delivery technology from University of Washington that encompasses aspects of the polymeric carriers used in this study.
PY - 2014/6/19
Y1 - 2014/6/19
N2 - Because apoptosis of infected cells can limit virus production and spread, some viruses have co-opted prosurvival genes from the host. This includes the Epstein-Barr virus (EBV) gene BHRF1, a homolog of human Bcl-2 proteins that block apoptosis and are associated with cancer. Computational design and experimental optimization were used to generate a novel protein called BINDI that binds BHRF1 with picomolar affinity. BINDI recognizes the hydrophobic cleft of BHRF1 in a manner similar to other Bcl-2 protein interactions but makes many additional contacts to achieve exceptional affinity and specificity. BINDI induces apoptosis in EBV-infected cancer lines, and when delivered with an antibody-targeted intracellular delivery carrier, BINDI suppressed tumor growth and extended survival in a xenograft disease model of EBV-positive human lymphoma. High-specificity-designed proteins that selectively kill target cells may provide an advantage over the toxic compounds used in current generation antibody-drug conjugates.
AB - Because apoptosis of infected cells can limit virus production and spread, some viruses have co-opted prosurvival genes from the host. This includes the Epstein-Barr virus (EBV) gene BHRF1, a homolog of human Bcl-2 proteins that block apoptosis and are associated with cancer. Computational design and experimental optimization were used to generate a novel protein called BINDI that binds BHRF1 with picomolar affinity. BINDI recognizes the hydrophobic cleft of BHRF1 in a manner similar to other Bcl-2 protein interactions but makes many additional contacts to achieve exceptional affinity and specificity. BINDI induces apoptosis in EBV-infected cancer lines, and when delivered with an antibody-targeted intracellular delivery carrier, BINDI suppressed tumor growth and extended survival in a xenograft disease model of EBV-positive human lymphoma. High-specificity-designed proteins that selectively kill target cells may provide an advantage over the toxic compounds used in current generation antibody-drug conjugates.
UR - http://www.scopus.com/inward/record.url?scp=84903142850&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903142850&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2014.04.034
DO - 10.1016/j.cell.2014.04.034
M3 - Article
C2 - 24949974
AN - SCOPUS:84903142850
SN - 0092-8674
VL - 157
SP - 1644
EP - 1656
JO - Cell
JF - Cell
IS - 7
ER -